Friday, April 27, 2007

An opinion piece in the Harvard Crimson (student newspaper) by GREGORY N. PRICE and ELIZABETH M. STARK pleas for students to lend more support to the Open Access movement. It is a well thought out piece and worth a look. I particuarly like the proposal for students to make their senior theses available somehow and for students to write letters to Congress supporting OA.

Thursday, April 26, 2007

Really interesting blog, with a collection of other information is available from Coturnix at Science Blogs. Basically the discussion revolves around the use of figures from non Open Access publications. She writes:

My esteemed colleague here at scienceblogs, Shelley Batts of the Retrospectacle blog, did what we all do all the time - what is one of the primary role of science blogs: compared what a scientific paper says to what the press releases and media say about the paper. It was a paper widely reported by the press about the potential health effects of drinks like daikiri. Shelley wrote in her post that the paper is fine, but that the media coverage is faulty (what's new?). In order to demonstrate what the paper really says, she, as we often do, reprinted a table and one panel of a figure from the paper in her post.

The blog has lots of links to other blogs about this issue. My favorite line:

The old model will crumble and the dinosaurs can choose to adapt or go extinct.

Overall, I found the Sunday night talks very useful to set the stage. The introductory talks by the representatives from NHGRI, NIAID, and NIDDK clearly indicated that NIH as well as others consider the human microbiome an incredibly important research area. Then Jim Tiedje gave a nice overview of the recent NAS report on metagenomics (which was about metagenomics in general, not specifically for the human microbiome). The main points of the report are basically: microbes rule the world, metagenomics is a very powerful tool in studying them, and there is a need for a more coordinated effort among funding agencies to push metagenomics as a tool and a field. (My only complaint about Tiedje's presentation was he kept using the term "higher organisms" for those multicellular species with nuclei. But otherwise, he did a good job of concicely summarizing the report and the benefits as well as challenges of metagenomics).

Francis Collins then gave an overview of the NIH Roadmap Program. The Roadmap was started in ~2003 as an initaitive to identify projects that would need coordination across multiple NIH agencies. These projects should meet certain characteristics: truly transforming, require all NIH, must need incubator scape, and the outcome should produce material into the public domain. Collins then discussed how, from among hundreds of suggestions, the Human Microbiome was picked as one of five topic areas for in depth consideration for the new round of Roadmap competition. Thus the point of this workshop was to discuss this in more detail and help provide material and ideas for the full consideration of an HMP program.

I should note, I found one thing disappointing in the introduction which was a response to my question concerning whether this project would be limited only to studies of humans or would allow for studies of model systems that inform human work. The answer was basically that this would likely be limited to humans. I think this is a big mistake. The human genome project came to the realization that comparative studies with other species were critical to understanding and interpreting studies of the human genome. The same will be true of the human microbiome program.

Jeff Gordon then gave an overview of human microbiome studies, and focused on what are the key questions that need to be answered. Among the key questions: Do we share a core set of microbes? How should we view differences in microbes between people and over time? How do we relate communities of microbes to health and disease? How should we sample microbial communities to characterize them? What determines robustness of microbial communities in people?

To start to answer these and other questions, he suggested that we have three tiers of data collection: (1) deep draft assemblies of microbial communities and reference genomes, (2) reference microbiome work (deep characterization of individuals including information about the familiy history and genetics) (3) 16s surveys of communities (a global human microbial diversity survey). I basically liked all of his ideas. He did talk about work in model organisms too. His work has shown just how important this is ... and I think as I said above it needs to be emphasized more in the HMP.

David Relman, from Stanford, then talked about patterns in human microbial diversity. He talked about some of the challenges in such studies as well as results of his and others work. He discussed many interesting aspects of the diversity of samples, and the shapes of diversity. Some of the patterns he emphasized were that history plays a role in the diversity, that archaea generally seem to have limited presence, that diversity is uneven and complex.

Then Gary Huffnagle discussed in more detail the interaction of microbes with the host immune system. And Jo Handelsman discussed what she calls functional metagenomics, which involves focusing on the functions of genes found in the environment on top of examining the phylogenetic diversity of communities. Unfortauntely, I did not take extensive notes for these two talks so do not have much to base my comments on here. In addition, I confess, the fact that the room in which the meeting was held was incredibly crowded and boiling hot, and the fact that I had flown in from California earlier in the day, made taking notes challenging at this point. However, that did not stop me from going out afterwards for a beer with Julian Parkhill, Ewan Birney, Owen White, and Jacques Ravel. The worst part of going out for the beer - I grew up in Bethesda but I made multiple wrong turns in the two blocks to the brew pub. I am sure from now on Julian and Ewan will never trust my directions. Fortunately, the fact that the pub had the RedSox pummeling the Yankees on TV made up for my direction problems.

Monday, April 23, 2007

Jonathan Badger on his blog has a good little blurb about how he cannot examine a recent piece of research because his institution does not have a subscription to the journal. So the authors lose a reader becuase they published in a non OA journal. Worth a little read for microbiologists since many may not have access to the journal Geology where the paper was published. But the paper was about a fossil that may have been of a fungus.

I am currently attending a workshop sponsored by NIH in which the participants are discussing whether there should be a Human Microbiome Project, and if so, what that should mean.

First, what is generally meant by the "Microbiome." In essence the humn microbiome is the sum collection of all the microbes found in or on people. The human microbiome has become an important research field because the microbes that live in and among us play critical roles in human disease and health. An important aspect of this is the idea that microbes can be and are beneficial. For example, in the gut the normal microbes help with digestion and nutrient absorption as well as protect from infection. In addition, a variety of diseases (e.g., IBD, Krohns) seem likely to be caused by disruption in the normal microbial flora. In general, it seems likely that other ailments, like autoimmune diseases, allergies, etc will be found to have a connection to disruptions in the beneficial microbes that live among us.

Because of the importance of beneficial / commensal microbes in human biology, there have been growing efforts to characterize the microbes in various body locations - gut, mouth, lungs, skin, etc. But the efforts so far have simply given a tantalizing taste of how interesting and important these microbes are. So here comes this meeting. Organized by NIH (specifically, Francis Collins at NHGRI), this workshop is geared to discuss the possibility that studies of the human microbiome will be included in the next list of "NIH Roadmap" programs. More on the NIH Roadmap some other time.

Basically, the general idea is - do we need an big scale, organized program to tackle the human microbiome.? To get us in the mood, we had talks by many of the pioneers/leaders in the field (e.g., David Relman, Jeff Gordon, Jim Tiedje) as well as discussion of the NIH Roadmap program. I personally did not need any convincing but it was good to hear some of the ideas presented. In the end, I think there is no doubt that a large scale Human Microbiome Program is needed and would be very beneficial.

One of the reasons that an organized effort is needed is that studies of the human micribome are difficult. Reasons for this include:

1. Many of the microbes in the human system have not, and maybe cannot, be grown in isolation in the lab

2. The key features of the microbiome are determined by by populations of microbes and thus even if a representative of a species could be grown in the lab, it would not represent all the diversity in the population.

3. The best way to sample the populations is via "metagenomic" sequencing which involves isolating DNA and sequencing it directly without culturing.

4. Many of the important sites contain hundreds of species each with significant variation within species.

5. There likely will be ENORMOUS variation in and among people. Within a person, there will be variation over time as well as great variation in different sites. On top of that there will be great variation between people.

Given these and other complications, it seems a no brainer there is a need for a coordinated project to gather background information about the human microbiome that would then be useful to researchers, much like the human genome was useful to many researchers. So what would such a project do? Here are some possibilities

1. Sequence many "reference genomes." By reference genomes here I mean genomes of cultured isolates that are closely related to organisms known in various human locations.

2. Do metagenomic sequencing of a variety of human mcirobiome samples.

3. Conduct large scale human microbiome diversity studies. This could involve rRNA PCR surveys as well as some amount of genome sequencing.

4. Develop the computational tools needed to analyze the massive amounts of data that will come out.

5. Encourage the development of new methods to aid in studies of the microbiome.

So today I guess we will be discussing what specific things are needed in more detail. But again, even though I do not really work on human microbiome projects much, I think it is pretty clear that the time is right for a Human Microbiome Program. And importantly, the methods and tools and discoveries that could come from this will be of use in all studies of microbes in the environment.

Thursday, April 19, 2007

Just saw this very cool paper in PLoS Biology on Wolbachia that appear to have converted from parasites to mutualists. Wolbachia are among my favorite organisms. They are intracellular bacteria that have been found to infect a wide diversity of invertebrate species. In many cases, the Wolbachia have male specific detrimental effects (I like to call the WMDs - Wolbachia of male destruction). In other cases (e.g., in filiarial nematodes), Wolbachia appear to be beneficial.

I had heard about the work in the new paper from one of the authors Michael Turelli, who was one of the main people to convince me to move to Davis. In this study, the authors returned to examine a population of Drosophila simulans that Turelli had studied some 20 years ago. In the previous studies Turelli and colleagues had found a "classic case" of Wolbachia infection spreading in nature. When they returned to study the population and did a suite of experiments, they found that the Wolbachia had acquired fecundity increasing mutations, making them mutualistic.

Though they have not yet figured out what mutations occurred, it seems that a little genome sequencing might help them. Just a little selfish plug there, since I led the first project to sequence a Wolbachia genome and would love to do some more ...

Wednesday, April 18, 2007

I read with fascination an article in the New York Times magazine this weekend on Pop Culture entitled "Is Justin Timberlake a Product of Cumulative Advantage?" No, I was not fascinated by the Timerlake part. But what was interesting was Duncan Watt's argument that it is very difficult to predict the success or failure of entities in pop culture. He presented a model that is summarized as "The cumulative advantage:"

The reason is that when people tend to like what other people like, differences in popularity are subject to what is called “cumulative advantage,” or the “rich get richer” effect. This means that if one object happens to be slightly more popular than another at just the right point, it will tend to become more popular still

He then described an experiment they performed that was published in Science last year where

more than 14,000 participants registered at our Web site, Music Lab (www.musiclab.columbia.edu), and were asked to listen to, rate and, if they chose, download songs by bands they had never heard of. Some of the participants saw only the names of the songs and bands, while others also saw how many times the songs had been downloaded by previous participants. This second group — in what we called the “social influence” condition — was further split into eight parallel “worlds” such that participants could see the prior downloads of people only in their own world. We didn’t manipulate any of these rankings — all the artists in all the worlds started out identically, with zero downloads — but because the different worlds were kept separate, they subsequently evolved independently of one another.

They used this set up to test among two different possibilities.

First, if people know what they like regardless of what they think other people like, the most successful songs should draw about the same amount of the total market share in both the independent and social-influence conditions — that is, hits shouldn’t be any bigger just because the people downloading them know what other people downloaded. And second, the very same songs — the “best” ones — should become hits in all social-influence worlds. What we found, however, was exactly the opposite. In all the social-influence worlds, the most popular songs were much more popular (and the least popular songs were less popular) than in the independent condition. At the same time, however, the particular songs that became hits were different in different worlds, just as cumulative-advantage theory would predict. Introducing social influence into human decision making, in other words, didn’t just make the hits bigger; it also made them more unpredictable.

Why you may ask am I so fascinated by this? Well, what he described is mathematically and conceptually identical to Luria and Delbruck's fluctuation test (see my earlier blog about L & D), where they were testing the origin of mutants. Luria and Delbruck designed a test where they grew E. coli from the same starting point in different culture tubes. Then they exposed these tubes to selective pressures. If the number of mutants in the tubes were basically the same, this would mean that the mutants arose in response to the selection. If the number of mutants were vastly different (somehting they called a jackpot pattern) this would mean the mutants arose in the growth of the bacteria in the tubes prior to selection.

In the entertainment experiment, the different music "worlds" are the equivalent to the different test tubes. And the preferences of people are the equivalent of the selection. Their result in the music experiment was the jackpot pattern - the same thing seen by Luria and Delbruck. For Luria and Delbruck this meant selection did not guide mutation. For the music, this means the personal preference for the music has less influence than the random history of which music was picked early on.

Monday, April 16, 2007

OK - so here is my confession. I posted my blog last week about my brother's birthday to make up for my ditching him on his 40th birthday to go to a meeting at the Moore Foundation HQ. I really needed to go to this meeting, for many reasons, and so I went just for the day (driving from Davis did not take anywhere near as long as I expected --- just ~ 1.5 hours to the Presidio in SF where the Moore HQ is located). But with two kids including a newborn, I could not go to the A's Yankees game with my brother and so I posted that birthday blog to do something.

Anyway - not a ton to report from the meeting. It was the second California Metagenomics workshop organized by UCSD as part of the CAMERA project. The last one was in Berkeley. There were some good talks but as usual the best thing was a chance to talk to people in person. The two best talks in my opinion were one by Victoria Orphan from Caltech and one by Jessica Green from UC Merced. Orphan talked about a special sorting method they are using to pull out cells of particular organisms from environmental samples for subsequent gene and genome sequencing. Green talked about her work on spatial ecology and biogeography of microbes. I think we desperately need more people like Green in the microbial ecology field --- people who are taking methods and concepts used for "big" organisms and applying them to the microbial world (another example is Jen Martiny at Irvine who was not at the meeting but her husband Adam Martiny was there).

The most painful part of the meeting (other than the traffic on the way home) --- the lame behavior of many of the scientists in regard to our hosts the Moore Foundation. Despite being told many times that people were expected to bus their own tables --- few did. And even better, one of the participants (Adam Godzik) spent serious effort complaining about the coffee not being strong enough to the program officer from the Moore Foundation. And then asking her to get him some stronger coffee. Clearly he likes his coffee. But not really the best way to interact with a program officer.

Friday, April 13, 2007

Today is the 40th birthday of Michael Eisen, one of the co-founders of PLOS, an ardent supporter of Open Access in science, a top notch evolutionary and molecular biologist, and my brother. Happy Birthday Michael. In his honor, here are some links with information and stories about him:

Wednesday, April 11, 2007

Just saw the news about an article in PLoS Biology by Nancy Moran and colleagues. In their paper, which studied bacterial symbionts of aphids, they show that mutations in the gene encoding a heat shock protien in the symbiont influence the heat tolerance of the aphid hosts. Inturn this means that these mutations influence aphid geographical range and ecology. It is a relly cool story (Nancy Moran seems to publish a cool story like this every other week -- I feel lucky to have worked with her on one symbiont project which I have written about here).

To read more about the Moran work, go to the article, which anyone can read since it is in PLoS Biology. Or go to the press releases such as here.

Friday, April 06, 2007

I have gotten this story from a million people (since April 1) and figured someone had to put it out there on the web ...

Scientist Reveals Secret of the Ocean: It's Him

By NICHOLAS WADE

Published: April 1, 2007

Maverick scientist J. Craig Venter has done it again.It was just a few years ago that Dr. Venter announced that the human genome sequenced by Celera Genomics was in fact, mostly his own.And now, Venter has revealed a second twist in his genomic self-examination.Venter was discussing his Global Ocean Voyage, in which he used his personal yacht to collect ocean water samples from around the world.He then used large filtration units to collect microbes from the water samples which were then brought back to his high tech lab in Rockville, MD where he used the same methods that were used to sequence the human genome to study the genomes of the 1000s of ocean dwelling microbes found in each sample.In discussing the sampling methods, Venter let slip his latest attack on the standards of science – some of the samples were in fact not from the ocean, but were from microbial habitats in and on his body.

“The human microbiome is the next frontier,” Dr. Venter said.“The ocean voyage was just a cover.My main goal has always been to work on the microbes that live in and on people.And now that my genome is nearly complete, why not use myself as the model for human microbiome studies as well. ”

It is certainly true that in the last few years, the microbes that live in and on people have become a hot research topic.So hot that the same people who were involved in the race to sequence the human genome have been involved in this race too.Francis Collins, Venter main competitor and still the director of the National Human Genome Research Institute (NHGRI), recently testified before Congress regarding this type of work. He said, “There are more bacteria in the human gut than human cells in the entire human body… The human microbiome project represents an exciting new research area for NHGRI.”Other minor players in the public’s human genome effort, such as Eric Lander at the Whitehead Institute and George Weinstock at Baylor College of Medicine are also trying to muscle their way into studies of the human microbiome.

But Venter was not going to have any of this. “This time, I was not going to let them know I was coming.There would be no artificially declared tie.We set up a cutting edge human microbiome sampling system on the yacht, and then headed out to sea.They never knew what hit them. Now I have finished my microbiome.”

Reactions among scientists range from amusement to indifference, most saying that it is unimportant whose microbiome was sequenced. But a few scientists expressed disappointment that Dr. Venter had once again subverted the normal system of anonymity.Recent human microbome studies by other researchers have all involved anonymous donors.Jeff Gordon, at the Washington University in St. Louis expressed astonishment, “I have to fill out about 200 forms for every sample.It takes years to get anything done.And now Venter sails away with the prize.All I can say is, I will never listen to one of my review boards again.”

Venter had hinted at the possibility that something was amiss in an interview he gave last week for the BBC News.He said “Most of the samples we studied were from the ocean but a few were from people.”When the interviewer seemed stunned, Doug Rusch, one of Venter’s collaborators stepped in and said “Collected with the help of other people.”

Venter was apparently spurred to make the admission today that many of the samples were in fact from his own microbiome due to a video that surfaced on YouTube showing Jeff Hoffman, the person responsible for collecting the water samples, performing a tooth scraping of Venter and then replacing the ocean water filter with Venter’s tooth sample.

Venter said the YouTube video was immaterial, “Well, we wanted to wait a few more weeks to have the papers describing the human microbiome published.But in the interest of human health we are deciding to make the announcement today.”

Unlike with the human genome data however, Venter says all of the data from his personal microbiome will be made publicly available with no restrictions.“If there is one lesson I have learned it is that open access is better than closed access.The more people can access my microbiome, the more they will help me understand myself.Plus, unlike Collins and Lander, who publish only in fee-for access journals, we will be publishing our analysis in the inaugural issue of a new Open Access journal that is a joint effort between the Public Library of Science and Nature.It will be called PLoN, the Public Library of Nature.”

In making his microbiome available, Venter has yet again abandoned his genetic privacy as he did when making his own genome available.Interestingly, the microbiome helps explain one of the first findings that was announced regarding his own genome.Venter said that analysis of the samples that came from his intestine reveal that microbes may explain why even though he has an apoE4 allele in his own genome (which is associated with abnormal fat metabolism) he does not need to take fat-lowering drugs.“Apparently, I have some really good fat digesters living in my gut.They make up for what is missing in my own genome.”

Dr. Venter's reason for having his own microbiome sequenced, he said in the interview was in part scientific curiosity -- ''How could one not want to know about one's own microbes?'' As to opening himself to the accusation of egocentricity, he said, ''I've been accused of that so many times, I've gotten over it.''

The key question that remains is – which of the samples were really from the ocean and which are from Venter.Venter said “Our funding agencies, including the DOE and the Moore Foundation, have agreed that we should not explicitly reveal which samples are which as this will encourage people to develop better methods of analyzing such complex mixtures of different microbes.Next week we will be announcing an X-prize award for the person who can identify which samples are mine and where they came from in me.”

Rob Edwards, a freelance microbial genomics expert says “It won’t be difficult to tell which are which.In fact, we had already identified an anomalous sample from Venter’s previous ocean sampling work, but nobody would listen to us.”

Jonathan Eisen, an evolutionary biologist who used to work for Venter says “I am certain that a few creative evolutionary analyses can reveal which sample is which.In fact, we are starting analyzing the samples already in anticipation of the X-prize announcement.”

Others are not so confident.Ed Delong, an ocean microbiology expert from MIT says “We have spent years carefully selecting our ocean samples to make sure they are not contaminated with sewage from cruise ships or from city drains.And now this – a purposeful mixture of ocean and human. It could take years to clean up the mess.”

Venter does not seem concerned.“If nobody can figure out which sample is from me and which is from the ocean, then we have no hope of making any progress in studies of either human microbiomes or oceans.”

More importantly, many scientists want to know what Venter will do next.Some want to know so that they can make sure to stay out of the way.Others probably relish the potential to go head to head with Venter.In this regard, Venter is not shy.“Biofuels.There is a great future in biofuels.”

Thursday, April 05, 2007

In an article just published in the American Scientist, Alma Swan details a plethora of reasons for the importance of Open Access publishing. Alma says, for example:

The bickering over varied business models, and the side arguments over public access to publicly funded results, obscure a larger, more important question: Can open access—the fundamental change to a system where scientists no longer face barriers to accessing others' work (or their own)—advance science? My work involves measuring, analyzing and assessing developments in scholarly communication. From that perspective I argue that the answer is yes, and that the advance of science is the prime reason that access is an imperative.

AND

Open access can advance science in another way, by accelerating the speed at which science moves

AND

Open access can advance science in another way, by accelerating the speed at which science moves

Tuesday, April 03, 2007

Metagenomics has finally hit the big time. A story on metagenomics is on Slashdot.

Metagenomics studies begin by extracting DNA from all the microbes living in a particular environmental sample; there could be thousands or even millions of organisms in one sample. The extracted genetic material consists of millions of random fragments of DNA that can be cloned into a form capable of being maintained in laboratory bacteria. These bacteria are used to create a "library" that includes the genomes of all the microbes found in a habitat, the natural environment of the organisms. Although the genomes are fragmented, new DNA sequencing technology and more powerful computers are allowing scientists to begin making sense of these metagenomic jigsaw puzzles. They can examine gene sequences from thousands of previously unknown microorganisms, or induce the bacteria to express proteins that are screened for capabilities such as vitamin production or antibiotic resistance.

There is some bizarre stuff in there but hey that is OK. This is linking to a story in Science Daily about metagenomics which in itself is based on a National Academy Report on the field. The NAS report is definitely worth looking at.

The people who ran the committee are a who's who of the field including the chairs, Jo Handelsman (who coined the term metagenomics) and Jim Tiedje who is one of the grand gurus of environmental microbiology.

Citing this paper allows me to pay tribute to the journal in which it was published: PLoS Medicine, one of several journals published by the Public Library of Science. This is a journal of fine quality founded by people who believe that all readers (you, me, and doctors in poor countries) should have free access to the journal's entire contents—not just the abstracts. Peer review is just as stringent as in traditional journals that charge for online viewing. The PLoS way is the way every medical and scientific journal should be published. I'd love to persuade colleagues to submit their work first to a Public Library of Science journal and to go the limited-access route only if they must.